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Moving towards a metagenomic basis of therapeutics
Peter J. Turnbaugh, Ph.D. Harvard FAS Center for Systems Biology pturnbaugh@fas.harvard.edu NIH Microbiome Symposium: July 2013
Eggerthella lenta
A brief footnote in the pharmacology textbooks
“The microflora residing in the GI tract can metabolize a variety of drugs, which can reduce the amount available for absorption. Hydrolysis of esters and amides, reduction of double bonds, and nitro and diazo groups, dehydroxylation, dealkylation, deamination, acetylation, and esterification are some of [the] metabolic reactions mediated by gut microflora.”
– Handbook of Essential Pharmacokinetics, Pharmacodynamics, and Drug Metabolism for Industrial Scientists
“Drugs in the GI tract may be metabolized by the enzymes of the intestinal flora...before they gain access to the general circulation”
– Goodman & Gilman’s Pharmacological Basis of Therapeutics 12th edition
The gut microbiome influences drug metabolism
Haiser and Turnbaugh, Science 2012
Microbial activation of drugs for IBD and arthritis
Anti- inflammatory effects
Side effects
Haiser and Turnbaugh, Pharm. Res. 2012
Azoreductases are widely distributed in the human gut microbiome
• Can exploit these enzymes
to deliver compounds to the
distal gut
• Do variations in
azoreductase activity alter
drug efficacy?
Haiser and Turnbaugh, Pharm. Res. 2012
Gut microbes contribute to GI toxicity
• Structure solved for E. coli beta-glucuronidase
• High-throughput screening found 4 small molecule inhibitors
Wallace et al., Science 2010
Inhibitors work on multiple bacterial species
Wallace et al., Science 2010
Inhibitor rescues GI side effects
Wallace et al., Science 2010
Can microbial metabolites interfere with host drug metabolism?
O O
O S
OH O
NH
OH acetaminophen sulfate O
O
N O OH OH
acetaminophen O
N HO OHH
OH
acetaminophen glucuronide
• p-cresol is associated with post-dose S/G ratio
• Competes for sulfonation
• Could impact toxicity by removing a major detoxification
pathway
Clayton et al., PNAS 2009
Microbial colonization alters host gene expression
• Liver gene expression was altered in conventionally raised
mice relative to germ-free
• Significant changes to the length of anaesthesia during
treatment with barbituates
Bjorkholm et al., PLoS ONE 2009
Focusing in on the cardiac glycosides
Henry Haiser Foxglove
¡ Widely used drug for heart failure and arrhythmia
¡ Slows heart rate, increases force and velocity of contractions, via Na/K ATPase target
¡ Narrow therapeutic range: symptoms include blurred vision, GI problems (anorexia, nausea, diarrhea, vomiting), and cardiovascular dysfunction
Foxglove
Eggerthella lenta inactivates digoxin
SEM of E. lenta
• Serum concentration elevated by antibiotics
John Lindenbaum circa 1983; SEM from Saunders et al., 2009
Eggerthella lenta lives for arginine
Arginine inhibits digoxin reduction
Up-regulation of a cytochrome operon by digoxin
cgr operon is expressed at higher levels in low arginine conditions
Induction requires an unsaturated lactone ring
The cgr operon is unique to reducing strains
The cgr operon and two operons for sugar/small metabolite transport are missing from these two non-reducing strains
CGR ratio predicts digoxin reduction efficiency
Does dietary protein inhibit digoxin reduction?
• Arginine blocks digoxin reduction in vitro • Does this also occur in vivo?
Germ-free isolators:
Serum and urine digoxin levels altered by diet
• Serum and urine collected 4 hours following digoxin administration
• ELISA assay used to quantitate digoxin levels
Diet only significantly alters digoxin levels when colonized with the type strain of E.lenta
Model for digoxin inactivation by the human gut microbiome
See Poster P14 Haiser et al., Science 341, 295-298 (2013)
Needs and gaps
Need: gnotobiotics
Gaps: 1. Which bacterial taxa and metabolic pathways are involved? 2. How do microbial communities adapt to xenobiotics? 3. What are the relative contributions of host, microbial, and environmental
factors to pharmacokinetics and dynamics?
The grand challenge
Image credit: Suzy Parker, USA Today
Acknowledgements
Collaborators: Emily Balskus, Sunia Tranger (Harvard) Lynn Bry (HDDC Gnotobiotic Core) UNC Gnotobiotic Core
Funding from:
Visit us at turnbaugh.openwetware.org
Rachel
Henry
Kylynda An
Corinne
NIH, Harvard, General Mills, Ethicon, Harvard Digestive Disease Core
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